rs16030

Positions:

• chr19-13277090-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001127222.2(CACNA1A):​c.3861T>C​(p.Phe1287=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,608,954 control chromosomes in the GnomAD database, including 37,769 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2720 hom., cov: 31)
  • Exomes 𝑓: 0.22 (35049 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.776

Genes affected

CACNA1A (HGNC:1388): (calcium voltage-gated channel subunit alpha1 A) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 19-13277090-A-G is Benign according to our data. Variant chr19-13277090-A-G is described in ClinVar as [Benign]. Clinvar id is 128553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13277090-A-G is described in Lovd as [Benign]. Variant chr19-13277090-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.776 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3861T>C	p.Phe1287=	synonymous_variant	23/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3861T>C	p.Phe1287=	synonymous_variant	23/47	1	NM_001127222.2	ENSP00000353362

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26980 AN: 152008 Hom.: 2715 Cov.: 31

Gnomad AFR AF: 0.0947

Gnomad AMI AF: 0.0947

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.199

GnomAD3 exomes AF: 0.195 AC: 48395 AN: 248210 Hom.: 5025 AF XY: 0.201 AC XY: 27073 AN XY: 134782

Gnomad AFR exome AF: 0.0946

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.111

Gnomad SAS exome AF: 0.223

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.208

GnomAD4 exome AF: 0.216 AC: 314386 AN: 1456828 Hom.: 35049 Cov.: 30 AF XY: 0.217 AC XY: 157645 AN XY: 724870

Gnomad4 AFR exome AF: 0.0891

Gnomad4 AMR exome AF: 0.169

Gnomad4 ASJ exome AF: 0.194

Gnomad4 EAS exome AF: 0.126

Gnomad4 SAS exome AF: 0.226

Gnomad4 FIN exome AF: 0.218

Gnomad4 NFE exome AF: 0.225

Gnomad4 OTH exome AF: 0.204

GnomAD4 genome AF: 0.178 AC: 27010 AN: 152126 Hom.: 2720 Cov.: 31 AF XY: 0.177 AC XY: 13150 AN XY: 74360

Gnomad4 AFR AF: 0.0948

Gnomad4 AMR AF: 0.164

Gnomad4 ASJ AF: 0.182

Gnomad4 EAS AF: 0.121

Gnomad4 SAS AF: 0.221

Gnomad4 FIN AF: 0.223

Gnomad4 NFE AF: 0.225

Gnomad4 OTH AF: 0.202

Alfa AF: 0.215 Hom.: 6238

Bravo AF: 0.169

Asia WGS AF: 0.184 AC: 636 AN: 3478

EpiCase AF: 0.220

EpiControl AF: 0.221

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 29% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 27. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2021	- -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.0
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs16030; hg19: chr19-13387904; COSMIC: COSV64192867;